View source for TBX5 (gene)

{{Short description|Protein-coding gene that affects limb development and heart and bone function}}
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{{DISPLAYTITLE:''TBX5'' (gene)}}
{{Infobox gene}}
'''T-box transcription factor TBX5''', ('''T-box protein 5''') is a [[protein]] that in humans is encoded by the ''TBX5'' [[gene]].<ref name="pmid8988165">{{cite journal | vauthors = Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE | display-authors = 6 | title = Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome | journal = Nature Genetics | volume = 15 | issue = 1 | pages = 30–35 | date = January 1997 | pmid = 8988165 | doi = 10.1038/ng0197-30 | s2cid = 30763654 }}</ref><ref name="pmid8054982">{{cite journal | vauthors = Terrett JA, Newbury-Ecob R, Cross GS, Fenton I, Raeburn JA, Young ID, Brook JD | title = Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q | journal = Nature Genetics | volume = 6 | issue = 4 | pages = 401–404 | date = April 1994 | pmid = 8054982 | doi = 10.1038/ng0494-401 | s2cid = 30213 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TBX5 T-box 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6910}}</ref> Abnormalities in the TBX5 gene can result in altered limb development, [[Holt–Oram syndrome|Holt-Oram syndrome]], [[Tetra-amelia syndrome]], and cardiac and skeletal problems.

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the [[T-box]]. T-box genes encode transcription factors involved in the regulation of developmental processes.  This gene is closely linked{{clarify|date=April 2013}} to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12.

''TBX5'' is located on the long arm of [[chromosome 12]].<ref name="Patel C 2012">{{cite journal | vauthors = Patel C, Silcock L, McMullan D, Brueton L, Cox H | title = TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype | journal = European Journal of Human Genetics | volume = 20 | issue = 8 | pages = 863–869 | date = August 2012 | pmid = 22333898 | pmc = 3400730 | doi = 10.1038/ejhg.2012.16 }}</ref> ''TBX5'' produces a protein called T-box protein 5 that acts as a [[transcription factor]].<ref name="ReferenceA">{{cite journal | vauthors = Jhang WK, Lee BH, Kim GH, Lee JO, Yoo HW | title = Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations | journal = Cardiology in the Young | volume = 25 | issue = 6 | pages = 1093–1098 | date = August 2015 | pmid = 25216260 | doi = 10.1017/s1047951114001656 | s2cid = 43846874 }}</ref> ''TBX5'' is involved with forelimb and heart development.<ref name="Steimle_2017" /> This gene impacts the early development of the forelimb by triggering [[fibroblast growth factor]], [[FGF10]].<ref>{{cite journal | vauthors = Nishimoto S, Wilde SM, Wood S, Logan MP | title = RA Acts in a Coherent Feed-Forward Mechanism with Tbx5 to Control Limb Bud Induction and Initiation | journal = Cell Reports | volume = 12 | issue = 5 | pages = 879–891 | date = August 2015 | pmid = 26212321 | pmc = 4553633 | doi = 10.1016/j.celrep.2015.06.068 }}</ref>

== Function ==

''TBX5'' is a transcription factor that codes for the protein called T-box 5. The transcription factors it encodes are necessary for development, especially in the pattern formation of upper limbs and cardiac growth.<ref>{{cite web |title=TBX5 t-Box Transcription Factor 5 [Homo Sapiens (Human)] - Gene - NCBI. |url=https://www.ncbi.nlm.nih.gov/gene/6910 |work=National Center for Biotechnology Information |publisher=U.S. National Library of Medicine}}</ref> ''TBX5'' is involved with the development of the four [[heart chambers]], the electrical conducting system, and the septum separating the right and left sides of the heart.<ref>{{cite journal | vauthors = Boogerd CJ, Evans SM | title = TBX5 and NuRD Divide the Heart | journal = Developmental Cell | volume = 36 | issue = 3 | pages = 242–244 | date = February 2016 | pmid = 26859347 | pmc = 5542051 | doi = 10.1016/j.devcel.2016.01.015 }}</ref> Along with playing roles in the development of the heart, septum, and electrical system of the heart, it also activates genes that are involved in the development of the upper limbs, the arms and hands.

This gene is also involved in the muscle connective tissue for muscle and tendon patterning. A study showed that deletion of ''TBX5'' in forelimbs causes disruption in the muscle and tendon patterning without affecting the skeleton's development.<ref>{{cite journal | vauthors = Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, Mohun TJ, Logan MP | display-authors = 6 | title = Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning | journal = Developmental Cell | volume = 18 | issue = 1 | pages = 148–156 | date = January 2010 | pmid = 20152185 | pmc = 3034643 | doi = 10.1016/j.devcel.2009.11.013 | doi-access = free }}</ref> T-box protein 5 expression is in the cells of the lateral plate mesoderm which form the forelimb bud and the cascade of limb initiation. In its absence, no forelimb bud forms.

The encoded protein plays a major role in [[limb development]], specifically during [[limb bud]] initiation.<ref name="Tickle2015">{{cite journal | vauthors = Tickle C | title = How the embryo makes a limb: determination, polarity and identity | journal = Journal of Anatomy | volume = 227 | issue = 4 | pages = 418–430 | date = October 2015 | pmid = 26249743 | pmc = 4580101 | doi = 10.1111/joa.12361 }}</ref> For instance, in chickens Tbx5 specifies forelimb status.<ref>{{cite journal | vauthors = Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC | title = The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity | journal = Nature | volume = 398 | issue = 6730 | pages = 814–818 | date = April 1999 | pmid = 10235264 | doi = 10.1038/19769 | s2cid = 4330287 | bibcode = 1999Natur.398..814R }}</ref> The activation of Tbx5 and other [[T-box|T-box proteins]] by [[Hox genes]] activates signaling cascades that involve the [[Wnt signaling pathway]] and [[Fibroblast growth factor|FGF signals]] in limb buds.<ref name="Tickle2015" /> Ultimately, Tbx5 leads to the development of [[Apical ectodermal ridge|apical ectodermal ridge (AER)]] and [[Zone of polarizing activity|zone of polarizing activity (ZPA)]] signaling centers in the developing limb bud, which specify the orientation growth of the developing limb.<ref name="Tickle2015" /> Together with [[Tbx4]], Tbx5 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.<ref name="devcellmusc">{{cite journal | vauthors = Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, Mohun TJ, Logan MP | display-authors = 6 | title = Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning | journal = Developmental Cell | volume = 18 | issue = 1 | pages = 148–156 | date = January 2010 | pmid = 20152185 | pmc = 3034643 | doi = 10.1016/j.devcel.2009.11.013 }}</ref>

As a protein-coding gene, TBX5 encodes for the protein T-box Transcription Factor 5, which is a part of the T-box family of transcription factors. It also interacts with other genes, such as GATA4 and NKX2-5, and the BAF chromatin-remodeling complex to drive and repress gene expression during development.<ref name="pmid28057264">{{cite journal |vauthors=Steimle JD, Moskowitz IP |date=2017 |title=TBX5: A Key Regulator of Heart Development |journal=Current Topics in Developmental Biology |volume=122 |issue= |pages=195–221 |doi=10.1016/bs.ctdb.2016.08.008 |pmc=5371404 |pmid=28057264}}</ref>

=== Role in non-human animals ===
[[Knockout mouse|Mice that were genetically modified]] to not have the TBX5 gene did not survive gestation, due to the heart not developing past embryonic day ''E10.5''. Mice that only had one working copy of TBX5 were born with morphological problems such as enlarged hearts, atrial and ventral septum defects, and limb malformations similar to those found in the Holt-Oram Syndrome.<ref name="pmid14573514">{{cite journal | vauthors = Takeuchi JK, Ohgi M, Koshiba-Takeuchi K, Shiratori H, Sakaki I, Ogura K, Saijoh Y, Ogura T | display-authors = 6 | title = Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis | journal = Development | volume = 130 | issue = 24 | pages = 5953–5964 | date = December 2003 | pmid = 14573514 | doi = 10.1242/dev.00797 | s2cid = 209238 | doi-access =  }}</ref>

[[Domestic pigeon|Pigeons]] with feathered feet have ''Tbx5'' active in the hind feet, which cause them to develop feathered hindlimbs with thicker bones, more similar to their frontlimb wings.<ref>{{cite journal | vauthors = Boer EF, Van Hollebeke HF, Park S, Infante CR, Menke DB, Shapiro MD | title = Pigeon foot feathering reveals conserved limb identity networks | journal = Developmental Biology | volume = 454 | issue = 2 | pages = 128–144 | date = October 2019 | pmid = 31247188 | doi = 10.1016/j.ydbio.2019.06.015 | pmc = 6726567 }}</ref><ref>{{Cite web |title=Pigeon foot feather genes identified {{!}} UNews |url=https://unews.utah.edu/pigeon-foot-feather-genes-identified/ |access-date=2023-05-28 |website=unews.utah.edu |language=en-US}}</ref>

=== Role in human embyronic development ===
A gene "knockout" model for TBX5 by CRISPR/Cas9 genome editing has been created.<ref name="Zhao_2021">{{cite journal | vauthors = Zhao T, Bai R, Wu F, Lu WJ, Zhang J | title = Generation of a TBX5 homozygous knockout embryonic stem cell line (WAe009-A-45) by CRISPR/Cas9 genome editing | journal = Stem Cell Research | volume = 51 | issue =  | pages = 102156 | date = March 2021 | pmid = 33497883 | doi = 10.1016/j.scr.2021.102156 | s2cid = 231753691 | doi-access = free }}</ref>  This homozygous TBX5 knockout human embryonic stem cell line, called TBX5-KO maintained stem cell-like morphology, pluripotency markers, normal karyotype, and could differentiate into all three germ layers in vivo. This cell line can provide an in vitro platform for studying the pathogenic mechanisms and biological function of TBX5 in the heart development.<ref name="Zhao_2021" />  By understanding what happens in development without this gene, further treatment options for fetuses with a TBX5 mutation might be possible to prevent the severe cardiac defects associated with Holt-Oram Syndrome.

== Clinical significance ==

Mutations in this gene can result in Holt–Oram syndrome, a developmental disorder affecting the heart and upper limbs.<ref name="Virdis_2016">{{cite journal |vauthors=Virdis G, Dessole M, Dessole S, Ambrosini G, Cosmi E, Cherchil PL, Capobianco G |year=2016 |title=Holt Oram syndrome: a case report and review of the literature |journal=Clinical and Experimental Obstetrics & Gynecology |volume=43 |issue=1 |pages=137–139 |doi=10.12891/ceog3060.2016 |pmid=27048037 |s2cid=11803484 |doi-access=free}}</ref><ref name="Steimle_2017">{{cite journal | vauthors = Steimle JD, Moskowitz IP | title = TBX5: A Key Regulator of Heart Development | journal = Current Topics in Developmental Biology | volume = 122 | pages = 195–221 | year = 2017 | pmid = 28057264 | pmc = 5371404 | doi = 10.1016/bs.ctdb.2016.08.008 }}</ref> Holt-Oram syndrome can cause a hole in the septum,<ref name="ReferenceA" /> bone abnormalities in the fingers, wrists, or arms,<ref>{{cite journal | vauthors = Pizard A, Burgon PG, Paul DL, Bruneau BG, Seidman CE, Seidman JG | title = Connexin 40, a target of transcription factor Tbx5, patterns wrist, digits, and sternum | journal = Molecular and Cellular Biology | volume = 25 | issue = 12 | pages = 5073–5083 | date = June 2005 | pmid = 15923624 | pmc = 1140596 | doi = 10.1128/mcb.25.12.5073-5083.2005 }}</ref> and a conduction disease leading to abnormal heart rates and arrhythmias.<ref name="Patel C 2012" /> The most common cardiac issue associated with this condition is the malformation of the septum, which separates the left and right sides of the heart.<ref>{{cite web | title = Holt-Oram Syndrome | work =  Medlineplus Genetics | publisher = U.S. National Library of Medicine | date = 18 August 2020 | url = https://medlineplus.gov/genetics/condition/holt-oram-syndrome/#causes. }}</ref>

[[Tetra-amelia syndrome]] is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations.<ref>{{citation | vauthors = Niemann S | title=Tetra-Amelia Syndrome | chapter=Tetra-Amelia Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY |series=GeneReviews| publisher=University of Washington, Seattle | year=1993 | pmid=20301453 | url=http://www.ncbi.nlm.nih.gov/books/NBK1276/}}</ref> This condition can lead to the absence of one or both forelimbs.

Skeletally, there may be abnormally bent fingers, sloping shoulders, and [[phocomelia]]. Cardiac defects include ventral and atrial septation and problems with the conduction system.<ref name="pmid12668595">{{cite journal | vauthors = Packham EA, Brook JD | title = T-box genes in human disorders | journal = Human Molecular Genetics | volume = 12 Spec No 1 | issue = Spec No 1 | pages = R37–R44 | date = April 2003 | pmid = 12668595 | doi = 10.1093/hmg/ddg077 | doi-access = free }}</ref> Several transcript variants encoding different isoforms have been described for this gene.<ref name="entrez" />

== Interactions ==
TBX5 (gene) has been shown to [[Protein-protein interaction|interact]] with:
* [[GATA4]]<ref name = pmid12845333>{{cite journal | vauthors = Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D | display-authors = 6 | title = GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 | journal = Nature | volume = 424 | issue = 6947 | pages = 443–447 | date = July 2003 | pmid = 12845333 | doi = 10.1038/nature01827 | s2cid = 4304709 | bibcode = 2003Natur.424..443G }}</ref>  and
* [[NKX2-5]].<ref name = pmid12845333/><ref name = pmid11431700>{{cite journal | vauthors = Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I | title = Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation | journal = Nature Genetics | volume = 28 | issue = 3 | pages = 276–280 | date = July 2001 | pmid = 11431700 | doi = 10.1038/90123 | s2cid = 13250085 }}</ref>
{{clear}}

==References==
{{Reflist}}

== Further reading ==
{{Refbegin|30em}}
* {{cite journal | vauthors = Simon H | title = T-box genes and the formation of vertebrate forelimb- and hindlimb specific pattern | journal = Cell and Tissue Research | volume = 296 | issue = 1 | pages = 57–66 | date = April 1999 | pmid = 10199965 | doi = 10.1007/s004410051266 | s2cid = 44834807 }}
* {{cite journal | vauthors = Packham EA, Brook JD | title = T-box genes in human disorders | journal = Human Molecular Genetics | volume = 12 Spec No 1 | issue = Spec No 1 | pages = R37–R44 | date = April 2003 | pmid = 12668595 | doi = 10.1093/hmg/ddg077 | doi-access = free }}
* {{cite journal | vauthors = Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD | display-authors = 6 | title = Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family | journal = Nature Genetics | volume = 15 | issue = 1 | pages = 21–29 | date = January 1997 | pmid = 8988164 | doi = 10.1038/ng0197-21 | s2cid = 22619598 }}
* {{cite journal | vauthors = Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, Bruzzone R, Quadrelli R, Lerone M, Romeo G, Silengo M, Pereira A, Krieger J, Mesquita SF, Kamisago M, Morton CC, Pierpont ME, Müller CW, Seidman JG, Seidman CE | display-authors = 6 | title = Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 6 | pages = 2919–2924 | date = March 1999 | pmid = 10077612 | pmc = 15870 | doi = 10.1073/pnas.96.6.2919 | doi-access = free | bibcode = 1999PNAS...96.2919B }}
* {{cite journal | vauthors = Yang J, Hu D, Xia J, Yang Y, Ying B, Hu J, Zhou X | title = Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome | journal = American Journal of Medical Genetics | volume = 92 | issue = 4 | pages = 237–240 | date = June 2000 | pmid = 10842287 | doi = 10.1002/(SICI)1096-8628(20000605)92:4<237::AID-AJMG2>3.0.CO;2-G }}
* {{cite journal | vauthors = Hatcher CJ, Goldstein MM, Mah CS, Delia CS, Basson CT | title = Identification and localization of TBX5 transcription factor during human cardiac morphogenesis | journal = Developmental Dynamics | volume = 219 | issue = 1 | pages = 90–95 | date = September 2000 | pmid = 10974675 | doi = 10.1002/1097-0177(200009)219:1<90::AID-DVDY1033>3.0.CO;2-L | s2cid = 21081225 | doi-access =  }}
* {{cite journal | vauthors = Hatcher CJ, Kim MS, Mah CS, Goldstein MM, Wong B, Mikawa T, Basson CT | title = TBX5 transcription factor regulates cell proliferation during cardiogenesis | journal = Developmental Biology | volume = 230 | issue = 2 | pages = 177–188 | date = February 2001 | pmid = 11161571 | doi = 10.1006/dbio.2000.0134 | doi-access = free }}
* {{cite journal | vauthors = Cross SJ, Ching YH, Li QY, Armstrong-Buisseret L, Spranger S, Lyonnet S, Bonnet D, Penttinen M, Jonveaux P, Leheup B, Mortier G, Van Ravenswaaij C, Gardiner CA | display-authors = 6 | title = The mutation spectrum in Holt-Oram syndrome | journal = Journal of Medical Genetics | volume = 37 | issue = 10 | pages = 785–787 | date = October 2000 | pmid = 11183182 | pmc = 1757164 | doi = 10.1136/jmg.37.10.785 }}
* {{cite journal | vauthors = Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I | title = Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation | journal = Nature Genetics | volume = 28 | issue = 3 | pages = 276–280 | date = July 2001 | pmid = 11431700 | doi = 10.1038/90123 | s2cid = 13250085 }}
* {{cite journal | vauthors = Akrami SM, Winter RM, Brook JD, Armour JA | title = Detection of a large TBX5 deletion in a family with Holt-Oram syndrome | journal = Journal of Medical Genetics | volume = 38 | issue = 12 | pages = 44e–44 | date = December 2001 | pmid = 11748310 | pmc = 1734777 | doi = 10.1136/jmg.38.12.e44 }}
* {{cite journal | vauthors = He ML, Chen Y, Peng Y, Jin D, Du D, Wu J, Lu P, Lin MC, Kung HF | display-authors = 6 | title = Induction of apoptosis and inhibition of cell growth by developmental regulator hTBX5 | journal = Biochemical and Biophysical Research Communications | volume = 297 | issue = 2 | pages = 185–192 | date = September 2002 | pmid = 12237100 | doi = 10.1016/S0006-291X(02)02142-3 }}
* {{cite journal | vauthors = Fan C, Liu M, Wang Q | title = Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome | journal = The Journal of Biological Chemistry | volume = 278 | issue = 10 | pages = 8780–8785 | date = March 2003 | pmid = 12499378 | pmc = 1579789 | doi = 10.1074/jbc.M208120200 | doi-access = free }}
* {{cite journal | vauthors = Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D | display-authors = 6 | title = GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 | journal = Nature | volume = 424 | issue = 6947 | pages = 443–447 | date = July 2003 | pmid = 12845333 | doi = 10.1038/nature01827 | s2cid = 4304709 | bibcode = 2003Natur.424..443G }}
* {{cite journal | vauthors = Huang T, Lock JE, Marshall AC, Basson C, Seidman JG, Seidman CE | title = Causes of clinical diversity in human TBX5 mutations | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 67 | pages = 115–120 | year = 2003 | pmid = 12858531 | doi = 10.1101/sqb.2002.67.115 }}
* {{cite journal | vauthors = Collavoli A, Hatcher CJ, He J, Okin D, Deo R, Basson CT | title = TBX5 nuclear localization is mediated by dual cooperative intramolecular signals | journal = Journal of Molecular and Cellular Cardiology | volume = 35 | issue = 10 | pages = 1191–1195 | date = October 2003 | pmid = 14519429 | doi = 10.1016/S0022-2828(03)00231-1 }}
* {{cite journal | vauthors = Steimle JD, Moskowitz IP | title = TBX5: A Key Regulator of Heart Development | journal = Current Topics in Developmental Biology | volume = 122 | pages = 195–221 | year = 2017 | pmid = 28057264 | pmc = 5371404 | doi = 10.1016/bs.ctdb.2016.08.008 }}
{{Refend}}

== External links ==
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hos  GeneReviews/NCBI/NIH/UW entry on Holt-Oram Syndrome]
* {{MeshName|TBX5+protein,+human}}

{{Transcription factors|g4}}
{{Use dmy dates|date=April 2017}}

[[Category:Transcription factors]]